IL-22R (also known as IL-22R1 and IL-22RA) is a type II cytokine receptor selectively expressed on skin and epithelial cells. This receptor mediates signalling via three cytokines: interleukin 22 (IL-22), interleukin 20 (IL-20) and interleukin 24 (IL-24). Cytokine signalling via the IL-22R requires the formation of heterodimeric complexes at the cell surface. As shown in FIG. 1, IL-22 binds to and signals via a complex consisting of IL-22R and IL-10Rβ (also known as IL-10R2), whereas IL-20 and IL-24 bind to and signal via a heterodimeric complex consisting of IL-22R and IL-20Rβ (also known as IL-20R2).
Interleukin-22 is a cytokine expressed by immune cells, particularly activated dendritic cells and T cells. Once produced by the immune system, IL-22 exerts its biological effects by binding to and activating IL-22R on epithelial cells. Activation of the IL-22R-IL-10Rβ complex downstream of IL-22 binding leads to pro-inflammatory responses, the induction of anti-microbial proteins that are critical for host defense against bacterial pathogens, and protective effects in some organs such as the lungs and liver. IL-22 has also been implicated in disease pathology, particularly in the development of inflammatory disorders such as psoriasis, psoriatic arthritis and atopic dermatitis (Ma et al. J Clin. Invest. 118: 597-607 (2008); Van Belle et al. J Immunol. January 1; 188(1):462-9 (2012); Sabat et al. Nat. Rev. Drug Discov. 13(1): 21-38 (2014)).
The crystal structure of IL-22 in complex with the extracellular domain of IL-22R has been solved, and has provided important insights into how this ligand associates with its receptor (Jones et al. Structure 16(9): 1333-1344 (2008)). The extracellular region of IL-22R includes two fibronectin type III (FBNIII) domains (D1 and D2) oriented at approximately right angles to one another. Five loops located at the interface of these domains are primarily responsible for engaging IL-22 residues in the ligand-receptor complex. The IL-22 residues that contribute to receptor binding are clustered at two sites in the ligand, site 1a and site 1b. Insights into the critical residues contributed by both the receptor and the ligand have revealed ways in which this interaction could be disrupted to abrogate IL-22 signalling as a therapeutic strategy.
Interleukin-20 and interleukin-24 are expressed by monocytes and keratinocytes and similar to IL-22, these cytokines have been found to play a role in skin homeostasis and pathology. It follows, that strategies to inhibit or reduce signalling downstream of IL-22R by blocking the binding of ligands that activate this receptor could have therapeutic utility, particularly in the treatment of skin conditions such as psoriasis and atopic dermatitis.
Antibodies that bind to IL-22R and block the interaction between IL-22 and IL-22R have been developed. For example, WO2011/061119 describes a humanised IL-22R antibody produced from a mouse anti-human monoclonal antibody originally described in WO2006/047249. This humanised antibody, which will be referred to herein as “280-346-TSY” was shown to inhibit IL-22 signalling via IL-22RA in a cell proliferation assay, and inhibited IL-23-induced ear inflammation in a mouse model of psoriasis.